GenAge entry for MTOR (Homo sapiens)

Entry selected based on evidence directly linking the gene product to ageing in a mammalian model organism

Gene name (HAGRID: 221)

HGNC symbol

MTOR

Aliases

RAFT1; RAPT1; FLJ44809; FRAP; FRAP2; FRAP1

Common name

mechanistic target of rapamycin (serine/threonine kinase)

Potential relevance to the human ageing process

Main reason for selection

Entry selected based on evidence directly linking the gene product to ageing in a mammalian model organism

Description

The MTOR kinase belongs to the target of rapamycin group of enzymes which regulate cellular growth and proliferation [1318].
TOR enzymes, homologues of MTOR, have been linked to ageing in lower organisms. In yeast, deletions in the nutrient-responsive TOR pathway increased lifespan, and caloric restriction failed to further increase lifespan [1570]. Similarly, in roundworms, TOR deficiency more than doubled the lifespan [1319], and TOR disruption in fruit flies also extended lifespan [1317].

In invertebrates, a functional link between MTOR and insulin (INS)/IGF1 signalling has been proposed [1322], which further hints of a role for MTOR in ageing. Mice hypomorphic for mTOR have reduced mTOR expression, are smaller and live 20% longer [3258]. Female mice heterozygous for both mTOR and mLST8 also exhibit decreased mTORC1 activity and extended life span but have normal glucose tolerance and insulin sensitivity. While rapamycin also disrupts the mTORC2 complex, the lifespan extension is mediated through the mTORC1 complex [3628]. MTORC1 activity is reduced in the tissues of three long lived mice mutants: Snell dwarf mice due to a mutation in POU1F1, GHR knockout mice and PAPPA knock-out mice. Lowering mTOR enhances MGMT and NDRG1 levels, two proteins involved in DNA repair [4356].

In human cell cultures MTOR inhibition supresses the senescence associated secretory phenotype (SASP), which can disrupt tissues and contribute to age-related pathologies, including cancer. MTOR normally acts to regulate the SASP by promoting IL1A translation, which in turn promotes NFKB1 transcriptional activity [4337]. More work is needed to determine whether MTOR is associated with human ageing but it is a promising target for further research.